The human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS), a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive. Infection with HIV occurs by the transfer of blood, semen, vaginal fluid, pre-ejaculate, or breast milk. Within these bodily fluids, HIV is present as both free virus particles and virus within infected immune cells.
HIV infects vital cells in the human immune system such as helper T cells (specifically CD4+ T cells), macrophages, and dendritic cells. HIV infection leads to low levels of CD4+ T cells through a number of mechanisms, including apoptosis of uninfected bystander cells, direct viral killing of infected cells, and killing of infected CD4+ T cells by CD8 cytotoxic lymphocytes that recognize infected cells. When CD4+ T cell numbers decline below a critical level, cell-mediated immunity is lost, and the body becomes progressively more susceptible to opportunistic infections.
A number of therapeutic agents have been used to treat AIDS. Such agents include reverse transcriptase inhibitors (such as AZT), protease inhibitors (such as Indinavir) and integrase inhibitors (such as raltegravir.) However, although such agents have been shown to be affective, at least in the short term, their use may result in numerous side effects, for example, kidney problems and emergence of resistant viruses. As a result of these limitations, the development of new anti-HIV drugs having an alternative mechanism of action offers certain advantages.
Wnt ligands are small highly conserved glycoproteins consisting of 19 members approximately 35-50 kDa in size. They are produced by a variety of cell types and once secreted; can bind one of 10 Frizzled (Fzd) receptors on their target cells. Depending on the Wnt/Fzd combination, the result can be either a signal transduction cascade that is β-catenin-dependent (canonical pathway) or β-catenin independent. In the nucleus, β-catenin functions as a transcriptional/co-regulator where it binds to members of the LEF/TCF transcription factors to regulate gene expression. At the cell membrane, β-catenin functions as an adhesion protein contributing to cell structure and to cell-to-cell communication.
CD8+ T cells secrete a yet to be identified entity referred to as CD8 antiviral factor (CAF) that inhibits LTR-driven transcription of the HIV provirus in CD4+ T cells. The identity of CAF has remained elusive for over 30 years. Several key properties of CAF are known. CAF suppresses HIV replication at the level of transcription, it is stable at high temperature (56 for 20 min or 100 at 10 min) and low pH (2-8), and is secreted from activated CD8 T cells.